Index

Section A: Host Parasite Interactions

A1. Pathogenesis of bacterial diseases 2

A2. Recognition and entry processes of bacteria into host cell 3

A3. Bacterial toxins 7

A5. Recognition and entry processes of virus into host cell 12

A6. Cytopathic effects of viruses 16

A7. Virus induced cell transformation 17

A8. Cell- cell fusion in both normal and abnormal cells 18

Section B: Cell Signaling

B1. Signaling molecules 20

B2. Cell communication 23

B3. Cell receptors 26

B4. Secondary messengers 30

B5. G proteins in signal transduction 36

B6. Receptor protein-tyrosine kinases 42

B7. Cytokine receptors and non-receptor protein-tyrosine kinases 47

B8. Receptors linked to other enzymatic activities 48

B9. Bacterial and plant two component system 49

B10. Bacterial chemotaxis and quorum sensing 51

Section C: Haematopoiesis & Cell-Cell Interaction

C1. Regulation of haematopoiesis 55

C2: Cell adhesion and cell adhesion molecules (CAM) 58

C3. Cell-cell junctions 61

C4. The extracellular matrix 65

Section D: Cancer
D1. What causes cancer? 73

D2. Molecular genetics of cancer 73

D3. Oncogenes 79

D4. Multistep tumorigenesis 81

D5. Viruses and cancer 82

D6. Properties of cancer cells 84

D7. Interaction of normal cell with cancer cell 86

D8. Therapeutic interventions 86

Section E: Innate and Adaptive Immune System

E1. Cells and organs of the immune system 90

E2. Innate immune system 97

E3. Adaptive immune system 100

E4. Antigen and immunogen 103

E5. Antibodies/immunoglobulin 110

E6. Major histocompatibility complex and antigen presentation 116

E7. Cell-mediated immune responses 124

E8. Effector mechanisms of cell-mediated immunity 133

E9. Humoral immune responses 141

E10. Effector mechanisms of humoral immunity 148

E11. Transplant immunology 155

E13. Hypersensitivity 160

E14. Congenital and acquired immunodeficiency 166

E15. Immunity to microbes 170

E16. Vaccination 179

 CELL COMMUNICATION AND CELL SIGNALING

A. HOST PARASITE INTERACTIONS At times an infectious organism can enter a latent state in
which there is no shedding of the organism and no
If a symbiont either harms or lives at the expense of symptoms present within the host. This latency can be
another organism (the host), it is a parasitic organism, either intermittent or quiescent. Intermittent latency is
and the relationship is called parasitism. In this exemplified by the herpes virus that causes cold sores
relationship the body of the host can be viewed as a (fever blisters). After an initial infection, the symptoms
microenvironment that shelters and supports the growth subside. However, the virus remains in nerve tissue and
and multiplication of the parasitic organism. The parasitic can be activated weeks or years later by factors such as
organism is usually the smaller of the two partners and is stress or sunlight. In a quiescent latency the organism
metabolically dependent on the host. There are many persists but remains inactive for long periods of time,
parasitic agents or organisms among the viruses, bacteria, usually for years. For example, the varicella‐zoster virus
fungi, plants, and animals. causes chickenpox in children and remains after the
disease has subsided. In adulthood, under certain
By convention, when the word parasite is used without conditions, the same virus may erupt into a disease called
qualification, it refers specifically to a protozoan or shingles.
helminthic (nematode, trematode, cestode) organism.
Several types of parasitism are recognized. If an organism The outcome of most host‐parasite relationships is
lives on the surface of its host, it is an ectoparasite; if it dependent on three main factors: (1) the number of
lives internally, it is an endoparasite. The host on or in organisms present in or on the host, (2) the virulence of
which the parasitic organism either attains sexual maturity the organism, and (3) the host’s defenses or degree of
or reproduces is the final host. A host that serves as a resistance. Usually the greater the number of organisms
temporary but essential environment for some stages of within a given host, the greater the likelihood of disease.
development is an intermediate host. In contrast, a However, a few organisms can cause disease if they are
transfer host is not necessary for the completion of the extremely virulent or if the host’s resistance is low. A
organism’s life cycle but is used as a vehicle for reaching a host’s resistance can drop so much that its own microbiota
final host. A host infected with a parasitic organism that may cause disease. Such a disease is sometimes called an
also can infect humans is called a reservoir host. Because, endogenous disease because the agent originally comes
by definition, parasitic organisms are dependent on their from within the host’s own body. Endogenous diseases can
hosts, the symbiotic relationship between the host and be a serious problem among hospitalized patients with
parasite is a dynamic one (Table 1). very low resistance.

The term virulence [Latin virulentia, from virus, poison]

refers to the degree or intensity of pathogenicity. It is
determined by three characteristics of the pathogen:
invasiveness, infectivity, and pathogenic potential.
Invasiveness is the ability of the organism to spread to
adjacent or other tissues. Infectivity is the ability of the
organism to establish a focal point of infection.

Pathogenic potential refers to the degree that the pathogen

When a parasite is growing and multiplying within or on a causes damage. A major aspect of pathogenic potential is
host, the host is said to have an infection. The nature of an toxigenicity. Toxigenicity is the pathogen’s ability to
infection can vary widely with respect to severity, location, produce toxins, chemical substances that will damage the
and number of organisms involved. An infection may or host and produce disease. Virulence is often measured
may not result in overt disease. experimentally by determining the lethal dose 50 (LD 50) or
the infectious dose 50 (ID50). These values refer to the dose
An infectious disease is any change from a state of health or number of pathogens that will either kill or infect,
in which part or all of the host body is not capable of respectively, 50% of an experimental group of hosts within
carrying on its normal functions due to the presence of an a specified period.
organism or its products. Any organism or agent that
produces such a disease is a pathogen. Its ability to cause It should be noted that disease can result from causes
disease is called pathogenicity. other than toxin production. Sometimes a host will trigger
exaggerated immunological responses (immunopathology)
A primary (frank) pathogen is any organism that causes upon a second exposure or chronic exposure to a microbial
disease in a healthy host by a direct interaction. antigen. These hypersensitivity reactions damage the host
Conversely, an opportunistic pathogen is an organism even though the pathogen doesn’t produce a toxin.
that is either normally free living, or a part of the host’s Tuberculosis is a good example of the involvement of
normal microbiota, but which may adopt a pathogenic role hypersensitivity reactions in disease.
under certain circumstances, such as when the immune
system is compromised.

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A1. PATHOGENESIS OF BACTERIAL DISEASES

The steps for infections by pathogenic bacteria include compete successfully with the host’s normal microbiota for
1. Maintain a reservoir. A reservoir is a place to live before essential nutrients. Specialized structures that allow
and after causing an infection. bacteria to compete for surface attachment sites also are
2. Initially be transported to the host. necessary for colonization. Bacterial pathogens and many
3. Adhere to, colonize, and/or invade the host. non pathogens adhere with a high degree of specificity to
4. Multiply (grow) or complete its life cycle on or in the particular tissues. Adherence factors called adhesins are
host or the host’s cells. one reason for this specificity (Table 2). Adhesins are
5. Initially evade host defense mechanisms. specialized molecules or structures on the bacteria’s cell
6. Possess the ability to damage the host. surface that bind to complementary receptor sites on the
7. Leave the host and return to the reservoir or enter a host cell surface. They are one type of virulence factor.
new host. Virulence factors are bacterial products or structural
components (e.g., capsules and adhesins) that contribute
The first five factors influence the degree of infectivity and to virulence or pathogenicity.
invasiveness. Toxigenicity plays a major role in the sixth.

1. Maintaining a Reservoir of the Bacterial Pathogen

All bacterial pathogens must have at least one reservoir.

The most common reservoirs for human pathogens are
other humans, animals, and the environment. Since the
source and/or reservoir of the pathogen is part of the
infectious disease cycle.

2. Transport of the Bacterial Pathogen to the Host

An essential feature in the development of an infectious

disease is the initial transport of the bacterial pathogen to
the host. The most obvious means is direct contact—from
host to host (coughing, sneezing, body contact). Bacteria
also are transmitted indirectly in a variety of ways.
Infected hosts shed bacteria into their surroundings. Once
in the environment bacteria can be deposited on various
surfaces, from which they can be either resuspended into
the air or indirectly transmitted to a host later. Soil, water,
and food are indirect vehicles that harbor and transmit
bacteria to hosts. Vectors and fomites (inanimate objects
that harbor and transmit pathogens) also are involved in
the spread of many bacteria. 4. Invasion of the Bacterial Pathogen

3. Attachment and Colonization by the Bacterial Only a few pathogens cause disease by colonizing surfaces;
Pathogen most have additional virulence factors that enable the
pathogen to invade tissues. The degree of invasiveness of
After being transmitted to an appropriate host, the a pathogen—its ability to invade and grow in host
bacterial pathogen must be able to adhere to and colonize tissues—is related to the virulence factors the pathogen
host cells and tissues. possesses and determines the severity of disease it
In this context colonization means the establishment of a produces.
site of microbial reproduction on or within a host. It does
not necessarily result in tissue invasion or damage.
Colonization depends on the ability of the bacteria to

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Some bacteria, such as pneumococci and other 5. Growth and Multiplication of the Bacterial
streptococci, release digestive enzymes that allow them to Pathogen
invade tissues rapidly and cause severe illnesses.
Streptococci produce the enzyme hyaluronidase, or For a bacterial pathogen to be successful in growth and
spreading factor. This enzyme digests hyaluronic acid, a reproduction (colonization), it must find an appropriate
gluelike sub stance that helps hold the cells of certain environment (nutrients, pH, temperature, redox potential)
tissues together (Figure 1a). Digestion of hyaluronic acid within the host. Those areas of the host’s body that
allows streptococci to pass between epithelial cells and provide the most favorable conditions will harbor the
invade deeper tissues. In some cases the same pathogen pathogen and allow it to grow and multiply to produce an
can display varying degrees of invasiveness and infection.
pathogenicity in different tis sues. Both bubonic plague
and pneumonic plague are caused by the bacterium Some bacteria invade specific cells in which they grow
Yersinia pestis. In bubonic plague, the organisms enter the and multiply. Many of these intracellular pathogens have
body by means of a flea bite, migrate through the blood, evolved such elaborate nutrient‐ gathering mechanisms
and infect many organs and tissues. Untreated, this disease that they have become totally dependent on the host’s
has a mortality rate of about 55%. As a victim of cells. Finally, some bacteria can actively grow and multiply
pneumonic plague coughs or sneezes, the bacteria are in the blood plasma. The presence of viable bacteria in the
spread by aerosols to other in dividuals. bloodstream is called bacteremia. The presence of
bacteria or their toxins in the blood often is termed
septicemia [Greek septikos, produced by putrefaction, and
haima, blood].

6. Leaving the Host

The last determinant of a successful bacterial pathogen is

its ability to leave the host and enter either a new host or a
reservoir. Unless a successful escape occurs, the disease
cycle will be interrupted and the microorganism will not
be perpetuated. Most bacteria employ passive escape
mechanisms. Passive escape occurs when a pathogen or its
progeny leave the host in feces, urine, droplets, saliva, or
desquamated cells.

A2. RECOGNITION AND ENTRY PROCESSES OF BACTERIA

INTO HOST CELL:

For intracellular bacteria, entry into host cells represents

the central requirement for survival in, as well as
elimination by, the host. Host cell-directed uptake, called
Most bacteria that invade tissues damage cells and are
phagocytosis, is a feature of the so-called professional
found around cells. Thus, enzymes that contribute to tissue
damage are another important virulence factor. Coagulase phagocytes that comprise polymorphonuclear
granulocytes (PNGs) and marcrophages (MPs).
is a bacterial enzyme that accelerates the coagulation
(clotting) of blood. When blood plasma, the fluid portion of
blood, leaks out of vessels into tissues, coagulase causes Examples of bacteria that are engulfed by phagocytosis
include M. tuberculosis, L. pneumophila, and C. burnetii.
the plasma to clot. Staphylococcus aureus produces
Entry induced by the pathogen is termed invasion, which
coagulase to aid in infection (Figure 1b). Coagulase is a
two-edged sword: It keeps organisms from spreading but allows entry into nonphagocytic cells (nonprofessional
phagocytes).
also helps wall them off from immune defenses that might
otherwise destroy them. Conversely, the bacterial enzyme
streptokinase dissolves blood clots. Pathogens trapped in Salmonellae, shigellae, and listeriae are paradigms of
enteroinvasive pathogens. Contact between host cells and
blood clots free themselves to spread to other tissues by
pathogens proceeds either directly via receptor-ligand
secreting these virulence factors. Some bacterial
interactions or indirectly via deposition on the surface of
pathogens actually enter cells. The rickettsias, chlamydias,
and a few other pathogens must invade cells to grow, the pathogen of host molecules for which physiologic
receptors exist on the target cell.
reproduce, and produce disease. In other situations,
organisms that can survive within host phagocytic cells not
only escape destruction by the phagocytes but also obtain
free transportation to deeper body tissues. Such organisms
include Mycobacterium tuberculosis and Neisseria
gonorrhoeae.

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Depending on the cellular target, the final outcome of host Adhesion and Invasion
cell entry varies markedly.
1. Nonprofessional phagocytes are nonphagocytic, and Adhesion to mammalian cells is a prerequisite for
hence entry depends on expression of surface receptors extracellular colonization and for host cell invasion.
that can be exploited for invasion. Because of their low Bacterial adhesins that solely expedite adhesion to host
antibacterial activities, they primarily serve as a habitat. cells are expressed by numerous extracellular bacteria. In
2. PNGs are short-lived. Because they are highly phagocytic contrast, invasion-inducing molecules are a feature of
and express potent antibacterial activities constitutively, bacteria that permanently or transiently enter host cells.
uptake by PNGs is often fatal for the pathogen. Adherence to the cell membrane is based on protein-
3. Macrophages (MPs) are phagocytic and express medium protein interactions mediated by adhesins, such as
to high antibacterial activities depending on their internalins (bind E-cadherin) of L. monocytogens or
activation status. Accordingly, they serve both as habitat invasins (bind β1 integrins) from Yersinia. Adhesins may
and as effector cell. Following entry, bacterial pathogens be located on the bacterial surface or on pili. In addition,
begin intravacuolar life. adhesion may be induced by bacterial virulence factors,
which recruit fibronectin to attach to host cells by binding
Two main strategies are followed to avoid killing: to integrins. Although induced by the bacterium, invasion
1) avoidance of delivery to degradative lysosomes, either is ultimately a function of the host cell. Following adhesion,
by blocking phagosome maturation, divergence from the invasion can be induced in two ways. First, cell signaling
endocytic pathway to establish a vacuole with unique by host cell receptors that serve as targets of adhesion
features, or by escape into the cytosol; and induces uptake; second, uptake is induced independently
2) development of strategies to survive within acidic from the molecules that mediate adhesion. The term
degradative organelles. Certain bacteria have developed "zipper mechanism" refers to the first process. Bacterial
mechanisms that allow them to impede nutrient flow proteins interact with host cell surface proteins to mediate
inside the infected cell for their own benefit, to modulate internalization. This term has been suggested for the
generation of antimicrobial molecules, or to alter cell death highly selective receptor-mediated bacterial entry,
pathways. whereas the term "trigger mechanism" has been proposed
for indiscriminate, apparently adhesion-independent
In the following, the major steps from uptake to bacterial uptake. Bacterial effectors are delivered to the host cytosol
elimination by, or survival in, host cells will be described via a secretion system to induce bacterial entry.
(Figure 2).
1. Entry by Zipper Mechanisms

Host cell invasion by Yersinia and L. monocytogenes are

examples of invasion via the "zipper mechanism:' Receptor
binding induces phagocytic mechanisms in
nonprofessional phagocytes similar to those that are
constitutively operative in MPs. The eukaryotic cell
membrane tightly enwraps the bacterium and a cascade of
events, including protein phosphorylation, ubiquitination,
and phospholipid modifications then contribute to vacuole
genesis. Host entry of L. monocytogenes through the
intestinal epithelia is mediated by internalin on the surface
of this pathogen and E-cadherin on human epithelial cells.
Murine E-cadherin does not serve as a receptor for
intemalin due to an amino acid substitution in position 16.
Schwann cells, a major target of M. leprae, are shielded by a
basal lamina composed of laminin, collagen, and
proteoglycans. The unique tropism of M. leprae for
peripheral nerves appears to be due to bacterial binding to
laminin. This molecule, which serves as natural ligand for
integrins, thus provides a link between pathogen and
Schwann cell. Caveolin and lipid rafts serve as entry
portals for Brucella and certain strains of Chlamydia. More
recently, evidence was provided that clathrin-mediated
endocytosis contributes to entry of L. monocytogenes and
Rickettsia in a similar zipper mechanism. Septins, which
are small guanine triphosphatases (GTPases), are able to
form filaments and interact with actin to facilitate bacterial
entry as well.

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2. Entry by Trigger Mechanisms Phagocytosis and Phagosome Dynamics

Different molecules and mechanisms participate in host Phagocytosis of inert particles initiates a series of events
cell entry by S. enterica. Interactions between S. enterica that ultimately lead to the formation of a phagolysosome
and host cells causes large "membrane ruffling'' at the site (see Fig 1). Phagosome maturation is a strictly
of attachment followed by bacterial entry. Ruffling induces co-ordinated sequence of fusion and fission events, which
indiscriminate uptake even of other particles in the involves defined compartments of the endocytic pathway.
vicinity of S. enterica. This process has been termed Immediately after or even during phagosome sealing,
macropinocytosis. S. enterica triggers its uptake by phagosome maturation proceeds.
exploiting the signaling machinery of the host cell, thus  The early phagosome is characterized by a slightly
including cytoskeletal rearrangements. In certain mouse acidic to neutral pH (6.0 to 6.5) and membrane
cells, S. enterica induces phosphorylation of the receptor markers, such as MR, the tryptophane aspartate-
for the epidermal growth factor. Yet, S. enterica can also containing coat protein, and the transferrin
enter cells that do not express the epidermal growth factor receptor (TfR) with its ligand transferrin, small
receptor. This pathogen possesses two T3SS that allow it GTPase (Rab5), early endosomal antigen 1,
to directly manipulate intracellular molecules within host phosphatidylinositol 3-phosphate, and
cells. Syntaxin13.
• The late phagosome is characterized by a pH
Salmonella outer proteins are secreted into the host cells between 5.0 and 6.0 and the acquisition of the
rapidly after contact. Salmonella outer proteins activate vacuolar adenosine triphosphatase (ATPase)
the small GTP-binding protein cell division control proton pump (V-H+ATPase), mannose-6
(CDC42) of the Ras superfamily, which, in turn, induces the phosphate receptor, Rab-interacting lysosomal
reorganization of the actin cytoskeleton, thus promoting protein, and Rab7.
bacterial invasion through membrane ruffling. A homolog • The phagolysosome results from the fusion
of Salmonella outer protein (termed Salmonella outer between phagosomes and lysosomes,
protein 2) performs similar functions, and hence the two characterized by a pH between 4.0 and 5.5, high
molecules may partly compensate each other's functions. density of lysosome-associated membrane
The transiently intracellular pathogen proteins, and typical lysosomal enzymes (such as
cathepsins).
Shigella utilizes similar mechanisms for uptake via
membrane ruffling. More recently, filopodia were shown to The three stages form a continuum involving the sorting of
trap and direct shigellae to target cells in a process that membrane proteins, as well as budding of, and fusion with
involves bacterial type III secretion system(T3SS). other vesicles. During this dynamic process, the
Generally, modulators of the eukaryotic cell cytoskeleton phagosomes successively interact with the corresponding
are T3SS or T4SS products which modulate GTPase cycling endosomes and subsequently with lysosomes.
of proteins of the Rho, Rab, and Arf families.
Characterization of the Rab family of GTPases on vacuoles
Invasion of Nonprofessional Phagocytes harboring pathogens facilitates identification of the host
membrane transport pathways, which are turned on
Microbe-directed uptake allows entry into nonphagocytic during infection. M. tuberculosis and S. enterica interfere
cells and hence can be seen as an evasion mechanism of with the endocytic pathway by retaining Rab5 and Rab7,
phagocytosis by professional phagocytes. The target respectively, on their vacuoles. L. pneumophila, Brucella
spectrum of intracellular bacteria ranges from very broad abortus, and C. trachomatis interact with the secretory
to highly specific. M. leprae is found in a large variety of pathway as revealed by the presence of Rabl, Rab2, and
host cells and hence shows a broad target cell spectrum. L. Rab6, respectively, on their phagosomes.
monocytogenes enters the host through the gut epithelium
and its major target besides MPs is the hepatocyte; M. Acquisition of a vacuolar ATPase proton pump plays a
tuberculosis is almost, if not exclusively, restricted to MPs, central role in acidification of the phagosome. Immediately
although pneumocytes have been proposed as a safe niche after phagocytosis, the phagosome becomes alkaline for a
in the lung. It is noteworthy that intracellular bacteria are short time before acidification is initiated. The basic milieu
often capable of entering a variety of cell lines in vitro. is optimal for the activity of defensins and basic proteins,
These in vitro experiments do not necessarily reflect an in whereas the acidic pH is optimal for lysosomal enzymes.
vivo situation, and care should be taken in extrapolating Defensins are small (3.5 to 4.0 kD) peptides rich in
conclusions from them. For obligate intracellular bacteria, arginine and cysteine. They are abundant in PNG and
nonprofessional phagocytes rather than MPs represent the present in some, though not all, MPs (depending on species
preferred habitat. These bacteria are primarily found in and tissue location). Purified defensins are microbicidal for
endothelial and epithelial cells. certain intracellular bacteria, such as S. enterica and L.
monocytogenes.

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The contribution oflysosomal enzymes to bacterial killing attachment protein receptor to modulate membrane
is likely minor. Their major task is the degradation of transport. Legionella uses an array of proteins to control
already killed bacteria. These enzymes reside in the Rabl1 activity in the vacuole. Bacterial DrrA (SidM protein)
lysosome and are delivered into the phagosome during is a highly efficient guanine nucleotide exchange factor for
maturation through several independent waves, and they Rab1A. C. burnetii have evolved to live in the acidic late
reach their optimum activity during later stages, that is, in phagosome. Recent in vitro studies confirmed Coxiella's
the phagolysosome. requirement for low pH and oxygen tension. The fusogenic
properties of the vacuole are tightly regulated by the T4SS
Most intracellular bacteria interfere with phagosome apparatus, through ankirin proteins.
maturation and alter the phagosome in order to facilitate
their own survival (see Fig. 1). These include L. Egression into the Cytoplasm
pneumophila, M. tuberculosis, S. enterica, C. burnetii, and
Chlamydia. Although the specific mechanisms are Egress from the phagosomal into the cytoplasmic
incompletely understood, mycobacterial sulfatides and compartment represents a highly successful microbial
some mycobacterial glycolipids, most notably survival strategy because bacterial killing is focused on the
mannosylated lipoarabinomannans, impede phagolysosome to limit self-damage of MPs. This egression
phagolysosome fusion. has been extensively studied in L. monocytogenes, but is
known to be utilized by other intracellular pathogens,
Mycobacterial products, such as SapM and MptpB, including shigellae, rickettsiae, francisellae, and
contribute as well to the arrest of maturation of the early mycobacteria(see Fig. 1). Cytoplasmic invasion by L.
endosome. Antibody-coated M. tuberculosis organisms monocytogenes depends on listeriolysin (LLO), an SH-
lose their capacity to block discharge of lysosomal activated cholesterol-dependent cytolysin. LLO requires
enzymes, suggesting an auxiliary function of antibodies in activation by a host factor (gamma-IFN-inducible
cell-mediated protection against TB. Finally, the robust, lysosomal thiol reductase), a thiol reductase.
lipid-rich cell wall of mycobacteria renders them highly
resistant against enzymatic attack. M. tuberculosis, as well In the cytosol, LLO is degraded, thus avoiding killing of
as M. avium, arrest phagosome maturation at an early host cells. Deletion of the LLO gene (hly) renders L.
stage. They restrict phagosome acidification via the monocytogenes avirulent. LLO is also required for
exclusion of the V-H+ ATPase proton pump from the replication of L. monocytogenes in spacious listeria-
phagosome. Additional mechanisms may contribute to this containing phagosomes. These compartments are
event, such as NH4+ production by M. tuberculosis. nonacidic and allow slow replication of the pathogen.
Consistent with intraphagosomal NH4+ production, the Other molecules, such as phospholipase and lecithinase,
urease of M. tuberculosis is active at low pH. It has been are likely involved in membrane transition but are
known for some time that NH4+ also interferes with insufficient on their own. Invasion of L. monocytogenes into
phagosome-lysosome fusion. Exogenous adenosine the cytoplasmic compartment is markedly reduced in
triphosphate (ATP) has been shown to promote IFNγ-activated macrophages in which the microbe,
phagolysosome fusion resulting in concomitant death of entrapped in the phagosome, rapidly succumbs to attack
macrophages and killing of M. bovis bacillus Calmette- by toxic oxygen and nitrogen species and/ or defensins.
Guerin (BCG). Cytosol evasion of shigellae is mediated by factors, which
are also involved in bacterial entry (eg, IpaB, product of
Phagosome maturation is arrested somewhere between T3SS). Listeria simultaneously activates caspase-1 and
the early and late stages by M. tuberculosis, M. bovis BCG, L. consequently modulates death of infected cells via danger
pneumophila, S. enterica, and C. trachomatis, all of which signals represented by remnant vacuolar membranes. M.
replicate in non-acidified vacuoles. Phagosomes containing tuberculosis uses proteins encoded by the T7SS, located in
S. enterica, M. bovis BCG, or C. trachomatis appear the region of difference 1 gene region, to successfully
uncoupled from the maturation process through which translocate to the cytosol.
phagosomes containing inert particles proceed.
Cell-to-Cell Spreading
S. enterica remains in the spacious membrane-bound
phagosome, which is formed after uptake by the trigger L. monocytogenes is cleared from the blood by Kupffer cells
mechanism. Moreover, the bacteria manipulate the and then spreads to adjacent hepatocytes without
cytoskeleton via kinesin and tether the vacuole to reentering the extracellular milieu. Having entered the
membranes of the Golgi apparatus. The vacuole containing cytoplasm, L. monocytogenes induces a tail of host actin
C. trachomatis, which lacks any specific phagosome filaments, which push the bacterium forward to the outer
markers, is loaded with ATP, which is required by the region of the cell, where it induces pseudopod formation.
pathogen, by an unknown mechanism. In addition, Intracellular movement is achieved by coordinated actin
elements of the cytoskeleton (actin and filamin) are used polymerization at, and polarized release from, the
to stabilize the vacuole. L. pneumophila prevents fusion of bacterial surface.
the vacuole with the endosomal compartment and recruits
vesicles derived from Golgi and ER by use of the T4SS.
Moreover, Chlamydia employ mimics of soluble NSF

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The ActA gene encodes a 90-kDa protein located on the lipopolysaccharide (LPS) complexes, the components of
bacterial surface, which is responsible for these actin- which vary among genera. They are relatively stable
based movements. A host cytosolic complex composed of molecules that do not display affinities for particular
eight polypeptides has been identified which, on binding tissues. Bacterial endotoxins have nonspecific effects such
Act A, induces actin polymerization. The pseudopod- as fever or a sudden drop in blood pressure. They also
containing L. monocytogenes is engulfed by the adjacent cause tissue damage in diseases such as typhoid fever and
cell, and the microbe reaches the phagosome of the epidemic meningitis (an inflammation of membranes that
recipient cell, which is still endosed by cytoskeletal cover the brain and spinal cord).
material from the donor cell. The two plasma membranes
of the host and recipient cells apparently fuse, thereby Exotoxins are more powerful toxins produced by several
allowing the introduction of L. monocytogenes into the Gram-positive and a few Gram-negative bacteria. Most are
cytoplasm of the recipient cell. Thus, L. monocytogenes can polypeptides, which are denatured by heat, ultra violet
infect numerous cells without contacting extracellular light, and chemicals such as formaldehyde. Species of
defense mechanisms. Shigella use similar mechanisms for Clostridium, Bacillus, Staphylococcus, Streptococcus, and
evasion and intracellular movement, and a similar several other bacteria produce exotoxins.
spreading mechanism seems to be employed by S. enterica
and by R. rickettsii, but not by R. prowazekii and R. typhi. A A-B toxins were the first toxins to be studied intensively
role for motility and manipulation of host actin-based and are so named because they consist of two parts
structures was recently demonstrated for virulent designated A and B, both of which are polypeptides. Most
mycobacterium Bacterial T7SS mediates ejection from the exotoxins are A-B toxins. The A part is the active (enzyme)
infected host cell and facilitates spreading through actin component, and the B part is the binding component. An
structures coined "ejectosomes." example of an A-B toxin is the diphtheria toxin, which is
illustrated in Figure 3.
A3. BACTERIAL TOXINS  In the first step, the A-B toxin is released from the
bacterium.
A toxin is any substance that is poisonous to other  The B component attaches to a host cell receptor.
organisms. Some bacteria produce toxins, which are  The plasma membrane of the host cell invaginates
synthesized inside bacterial cells and are classified (folds inward) at the point where the A-B exotoxin
according to how they are released. Exotoxins are soluble and plasma receptor make contact, and the
substances secreted into host tissues. exotoxin enters the cell by receptor-mediated
Endotoxins are part of the cell wall and are released into endocytosis.
host tissues—sometimes in large quantities—from Gram  The A-B exotoxin and receptor are enclosed by a
negative bacteria, often when the bacteria die or divide. pinchedoff portion of the membrane.
Giving antibiotics that kill such bacteria can release  The A-B components of the exotoxin separate. The
sufficient toxin to cause the patient to die of severely A component alters the function of the host cell,
reduced blood pressure (endotoxic shock). often by inhibiting protein synthesis. The B
component is released from the host cell, and the
Let us look at some of the properties and effects of receptor is inserted into the plasma membrane for
endotoxins and exotoxins (Table 3). Relatively weak reuse.
(except in large doses), endotoxins are produced by
certain Gram-negative bacteria. All endotoxins consist of

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 CELL COMMUNICATION AND CELL SIGNALING

Rather, the hemolysins release iron from the hemoglobin

molecules in the red blood cells. Iron is a critical element
for growth of all cells, both host and microbe. But there is
very little free iron within the human body. Most of it is
bound in a form such as hemoglobin, and the microbe must
enzymatically release it. Bacteria that can produce
hemolysins can grow better than those that do not
produce these enzymes. Especially in the staphylococci,
the hemolysins can damage other types of cells as well.
Alpha-hemolysin damages smooth muscle and kills skin
cells.

Virulence factors called leukocidins are exotoxins

produced by many bacteria, including the streptococci and
staphylococci. These toxins damage or destroy certain
kinds of white blood cells called neutrophils and
macrophages. Leukocidins are most effective when
released by microbes that have been engulfed by a
neurophil. Because of the action of leukocidins, the num
ber of white blood cells decreases in certain diseases,
although most infections are characterized by an elevated
white cell count. A similar substance, called leukostatin,
interferes with the ability of leukocytes to engulf
microorganisms that secrete the exotoxin.

In the preceding examples, the spreading of exotoxins by

blood from the site of infection is called toxemia. But some
diseases caused by microbes are due not to infection and
invasion of tissues by pathogens but instead to the
ingestion of preformed toxins made by pathogens. For
example, botulism food poisoning strikes within hours of
ingesting food that contains a significant amount of toxin
produced by Clostridium botulinum—too short a time for
the microbe to invade tissues and cause disease. The toxins
accumulate during the storage of an improperly sterilized
jar or can of food and have an immediate and often
ultimately lethal effect on the consumer. Diseases that
result from the ingestion of a toxin are termed
intoxications rather than infections.

Superantigens are antigens that provoke a very intense

immune response. They are bacterial proteins. Through a
series of interactions with various cells of the immune
Some exotoxins are enzymes. Hemolysins were first system, superantigens nonspecifically stimulate the
discovered in cultures of bacteria grown on blood agar proliferation of immune cells called T cells. These cells are
plates. The action of these exotoxins is to lyse (rupture) types of white blood cells (lymphocytes) that act against
red blood cells. Two kinds of hemolysins were identified foreign organisms and tissues (transplants) and regulate
from bacteria grown on blood agar plates. the activation and proliferation of other cells of the
immune system. In response to superantigens, T cells are
Alpha-hemolysins (α-hemolysin) hemolyze blood cells, stimulated to release enormous amounts of chemicals
partially break down hemoglobin, and produce a greenish called cytokines. Cytokines are small protein molecules
ring around colonies; α -hemolysins also hemolyze blood produced by various body cells, especially T cells, that
cells but completely break down hemoglobin and leave a regulate immune responses and mediate cell-to-cell
clear ring around colonies. Streptococci and staphylococci communication. The excessively high levels of cytokines
produce different hemolysins that are helpful in released by T cells enter the bloodstream and give rise to a
identifying them in laboratory cultures. There is no number of symptoms, including fever, nausea, vomiting,
evidence that red blood cell lysis plays a role in the disease diarrhea, and sometimes shock and even death. Bacterial
syndrome. superantigens include the staphylococcal toxins that cause
food poisoning and toxic shock syndrome.

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